Summary: Parkinson's disease (PD) is the second most common neurodegenerative disease in world and incidence of the disease is expected to steadily rise. Levodopa therapy has been the standard treatment strategy for PD patients for nearly 60 years and while it is effective in alleviating many motor symptoms in the early stages of PD, I it is plagued by the induction of dyskinesia is late stage patients. Hence, there is a major medical need for 1) symptomatic therapies that do not have the side-effect profile of levodopa and 2) better therapeutic strategies for alleviating LID. Our central thesis is that striatal cholinergic interneurons (ChIs) are pivotal determinants of the striatal pathophysiology underlying both PD motor symptoms and LID ? making them prime targets for the development of new therapies. While it has long been appreciated that aberrant striatal cholinergic signaling is a contributing factor in the motor symptoms of PD, the mechanisms underlying this linkage have not been fully delineated. The mechanisms underlying LID are even less well understood. Current thinking has focused upon the direct actions of levodopa-derived dopamine (DA) on the principal neurons of the striatum. However, several lines of evidence, including new results presented in this application, suggest that a particular class of interneuron that releases acetylcholine is not just important, but necessary for LID. Moreover, our preliminary studies provide a mechanistic foundation for this observation, suggesting that alterations in the properties of principal neurons actually trigger aberrant activity in interneurons ? reconciling the two apparently discrepant scientific perspectives. In addition, our preliminary work establishes the importance of interneuron-dependent, striatal remodeling not only when striatal DA levels are high (so-called on-state), but also when DA levels are low and movement is so difficult (off-state). Far from being a passive period, the striatal circuitry is being distorted during this period, contributing to the severity of the dyskinesia during the next on-state. Indeed, an FDA-approved and well- tolerated drug when administered during the off-state significantly alleviates LID in a mouse model. But much remains to be done if these exciting new discoveries are to be translated into new treatments for PD patients. We propose to take advantage of a collection of new tools to pursue four specific aims in rodent models: 1) characterize the determinants of ChI activity and ACh release in PD and LID states; 2) characterize how ChI activity directly modulates SPNs in PD and LID states; 3) characterize how ChI activity indirectly modulates SPNs through intrastriatal GABAergic networks in LID states; 4) characterize how ChI activity remodels the functional connectomes of SPNs in PD and LID states. Although these aims are ambitious and beyond the reach of a modular R01, they are within the grasp of the outstanding, interactive team we have assembled for this non-modular proposal ? putting novel therapies for PD patients on the event horizon.